- Shahd Alqudah. - Moayyad Al-Shafei. - Malik Zihlif. 1 P a g e

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1 -5 - Shahd Alqudah - Moayyad Al-Shafei - Malik Zihlif 1 P a g e

2 The adverse effects of parental iron therapy: 1- Headache, light-headedness (the most important). 2- Fever, arthralgia, back pain. 3- Flushing, urticarial, bronchospasm, and rarely anaphylaxis and death. - Notes on these side effects: - The most important side effect you should focus on is the first one. - Regarding the third point: clinical data indicates that, the risk of anaphylaxis is largely associated with iron dextran formulations, which are no longer used (instead we use sucrose formulations). - Black stool is only seen with oral iron supplements. Acute iron toxicity: - Exclusively in young children, who accidentally ingest iron tablets why? This is mainly because iron pills look like candy sweets. - As few as 10 tablets can be lethal in young children. - The toxic dose depends on the body mass index of the child. - If iron toxicity occurs, iron will be oxidized leading to metabolic acidosis (the doctor said that metabolic acidosis will cause hypoxia and reduce the tissue blood supply which may cause death). - Children who are poisoned with oral iron experience necrotizing gastroenteritis, with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea. - Fast intervention is critical to save their lives. - In most poisoning cases charcoal is used as an adsorbent material. - In the case of iron toxicity, charcoal is ineffective as it doesn't adsorb iron, so don't ever think of giving charcoal in cases of iron toxicity. Management of acute iron toxicity: For the unabsorbed pills (we need to flush out unabsorbed pills): -Whole bowel irrigation should be performed, or the administration of a rapid acting emetic ipecac to perform what is called gastric lavage. For iron that has already been absorbed: Deferoxamine, a potent ironchelating compound, can be given systemically to bind the absorbed iron and promote its excretion in urine and feces. 2 P a g e

3 Appropriate supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided. Chronic iron toxicity (iron overload) hemochromatosis: - Excess iron is deposited in the heart, liver, pancreas, and other organs. It can lead to organ failure and death. - It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption. - And in patients who receive many red cell transfusions over a long period of time (e.g. patients with thalassemia major). - Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy (One unit of blood can be removed every week) until iron level is normalized. Megaloblastic anemias: - During erythropoiesis the cell increases the synthesis of both DNA and cytoplasmic components, it then divides (passing G2/M check point of the cell cycle). - But if the DNA synthesis is defected (which will impair the cell cycle progression from the G2 growth stage to the mitosis (M) stage, which is called G2/M arrest), it will lead to continuous cell growth but without division, which presents as macrocytosis. - Megaloblastic anemia,which is a marrow disorder caused by defective DNA synthesis, occurs due to the deficiency of either vitamin B12 or Folic acid.both are cofactors in DNA synthesis; because they catalyze the coupling reaction (transport of methyl group to homocysteine producing the methionine). Vitamin B12 deficiency anemia : - Vitamin B12 is readily absorbed in the last part of the small intestine (ileum), which leads to the large intestine. However, to be absorbed, the vitamin must combine with intrinsic factor, a protein produced in the stomach. - Anemia may result from: 1- Deficiency (strict vegetarians with no meat or dairy products intake). 2- Impaired absorption due to decreased intrinsic factor (Pernicious anemia). 3- Gastrectomy. 4- Malnutrition, RA, thyroid conditions. 3 P a g e

4 - B12 deficiency has two subsequent effects(symptoms): * Neurological syndrome. * Hematological abnormalities. - It can be distinguished from other anemias by its neurological syndrome: delirium, numbness, tingling of hand and feet, loss of fine learned movements, difficulty in walking, bladder and bowel dysfunction. - Neurological syndrome presents in early stages, examples: Constipation, glossitis, dizziness, numbness and others. - Patients should have very low levels of vit B12 to develop hematological abnormalities (late stages). - Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin. Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation. - Strategies of giving vitamin B12 supplementation as cyanocobalamin(they may change depending on the case and the prognosis): 1- A patient with observed B12 deficiency without neurological symptoms: We either give him an injection every week for a month, or one injection every three days for a month. We then measure the level of the vitamin, to determine what to do after. 2- A patient with profound deficiency ( <50 ng/ml) with neurological symptoms: We should act very fast and load the patient with b12 through: *a daily injection for a week, *a weekly injection for a month, then *a monthly injection for the rest of his life. [this is called maintenance therapy] - If neurologic abnormalities are present, maintenance therapy injections should be given every 1 2 weeks for 6 months before switching to monthly injections. (slides) - In the case of malabsorption, the patient may need lifelong injections; because he cannot absorb B12/intrinsic factor complex 4 P a g e

5 - Oral vitamin B12-intrinsic factor mixtures and liver extracts should not be used to treat vitamin B12 deficiency; however, daily oral doses of 1000 mcg of vitamin B12 are usually sufficient to treat patients with pernicious anemia, especially those who refuse or cannot tolerate the injections. (slides) Folic acid deficiency anemia: The following points weren t mentioned by the doctor, they are from the slides:. - Folic acid deficiency and megaloblastic anemia can develop within 1 6 months (low stored amount) after the intake of folic acid stops, depending on the patient's nutritional status and the rate of folate utilization. - Patients with alcohol dependence and patients with liver disease can develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. - Patients who require renal dialysis develop folic acid deficiency because folates are removed from the plasma during the dialysis procedure. - In large doses may counteract the effects of anticonvulsants potentially leading to seizures. - Its Adverse reactions are Erythema, itching, and rash. - Folic acid deficiency is linked to neural tube formation defects of the fetus. So, in Jordan, once the woman becomes pregnant, we put her on folic acid. Women who are considering having a child should be given folic acid 2 months before conception. - In Jordan, bread is fortified; they add folic acid to the bread, that s why we usually don t have folic acid deficiency in Jordan but keep it in your mind through the diagnosis of the patients. - It is given orally because it is well absorbed. - Anemia may be indistinguishable from B12 deficiency but occurs rapidly. - The level of folic acid must be evaluated before treatment. - Folate therapy will correct hematological abnormalities but not neurological problems. - **To avoid neurological complications of vitamin B12 deficiency, it is important to evaluate the basis of the megaloblastic anemia (is it due to the deficiency of vitamin B12 or folic acid?) prior to instituting therapy, 5 P a g e

6 because B12 deficiency may be masked by folate supplementation which can then proceed to severe irreversible neurologic dysfunction and disease. - After evaluating, if both vitamins are deficient we use a combination therapy. - The professor asked two questions: Are we allowed to prescribe vit b12 supplements even if there is no deficiency? And are b12 supplements indicated for the treatment of chronic fatigue syndrome? More information about these issues will be given in the next sheet. Anti-malarial drugs: - Malaria is an acute infectious disease caused by four species of the protozoal genus Plasmodium. It is transmitted to humans through the bite of a female Anopheles mosquito. - It's most commonly found in areas of South America, Africa, and Asia. - Fortunately, no malaria cases are found in Jordan. - Species are: P. Falciparum, P. Vivax, P. Malariae, and P. Ovale. - P. falciparum causes malignant tertian malaria. Malignant because it is the most severe form of malaria and can be fatal. Tertian because it is said to produce fever every third day. - P. vivax and P. ovale, both of which can produce dormant liver stage parasites. - P. vivax produces benign tertian malaria. Benign because it is less severe than falciparum and is seldom fatal. Life cycle: - Two Interdependent Life Cycles: Sexual cycle: in the mosquito Asexual cycle: in the human which includes: 1-The transmission to humans by mosquito bites. 2-Reaching the liver (Exoerythrocytic phase) where they become tissue Schizonts (active form) or Hypnozoites (latent or sleeping form), (remember that both P. vivax and P. ovale, can produce dormant liver stage parasites which mainly persist in the liver). 3- They then infect RBCs (Erythrocytic phase) where they will: a-live as blood schizonts (acute infection), b-or produce gametocytes that can be ingested through the mosquito bite repeating the cycle. 6 P a g e

7 Notes: - Drugs that eliminate developing or dormant liver forms are called tissue schizonticides. - Those that act on erythrocytic parasites are blood schizonticides; - And those that kill sexual stages and prevent transmission to mosquitoes are gametocides(notice that they kill gametocytes in the human body). - No single available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages. - Very important note:. - In the parasitic lysosomes, hemoglobin(globin+heme) is utilized in order to supply the parasite with amino acids necessary for its metabolism. - Free heme is extremely toxic for the parasite. It can generate ROS. And as it is lipophilic, it can intercalate into membranes causing cell lysis. - In order for plasmodium species to survive, free heme is metabolized to an inert chemical form called haemozoin by a process known as biomineralization. This critical step is targeted by most anti-malarial agents. - Chloroquie : - Its mechanism of action is complex and not fully understood. It accumulates in parasitic lysosomes. Chloroquine inhibits digestion of hemoglobin by the parasite and thus helps reducing its supply of amino acids. It also inhibits hame polymerase - the enzyme that polymerizes toxic free heme to the innocuous haemozoin. - It is the drug of choice in the treatment of erythrocytic P. falciparum malaria, except in resistant strains. - Chloroquine is less effective against P. vivax malaria.(remember that P. vivax produces dormant liver stage parasite) - Chloroquine is used for prophylaxis of malaria when travelling to areas with known chloroquine- sensitive malaria, by taking one tablet weekly. - It has a long tissue half-life, so tissue reservoir will be established and the drug is released slowly to the blood. - Treatment of malaria infection: - A loading dose of 200 mg/kg in the first day, then a dose of 10 mg/kg for the second and the third days. - Resistance for chloroquine has been developed, by pumping out the drug (in a very similar manner of tetracycline resistance). 7 P a g e

8 - Mefloquine, which is not a substrate for pump, is effective therapy for many chloroquine resistant strains of P falciparum and against other species. - Chloroquine side effects: At high doses, toxic effects occur, including gastrointestinal upset, pruritus, headaches, and visual disturbances which is mostly characterized by blurry vision (an ophthalmological examination should be routinely performed). - Parenteral administration is not approved because of the hypotension, cardiac arrhythmia, and convulsions. 8 P a g e

Hematopoiesis, The hematopoietic machinery requires a constant supply iron, vitamin B 12, and folic acid.

Hematopoiesis, The hematopoietic machinery requires a constant supply iron, vitamin B 12, and folic acid. Hematopoiesis, 200 billion new blood cells per day The hematopoietic machinery requires a constant supply iron, vitamin B 12, and folic acid. hematopoietic growth factors, proteins that regulate the proliferation